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Precision Medicine in Phaeochromocytoma and Paraganglioma.

ABSTRACT: Precision medicine is a term used to describe medical care, which is specifically tailored to an individual patient or disease with the aim of ensuring the best clinical outcome whilst reducing the risk of adverse effects. Phaeochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumours with uncertain malignant potential. Over recent years, the molecular profiling of PPGLs has increased our understanding of the mechanisms that drive tumorigenesis. A high proportion of PPGLs are hereditary, with non-hereditary tumours commonly harbouring somatic mutations in known susceptibility genes. Through detailed interrogation of genotype-phenotype, correlations PPGLs can be classified into three different subgroups or clusters. Thus, PPGLs serve as an ideal paradigm for developing, testing and implementing precision medicine concepts in the clinic. In this review, we provide an overview of PPGLs and highlight how detailed molecular characterisation of these tumours provides current and future opportunities for precision oncology.

SUBMITTER: Winzeler B

PROVIDER: S-EPMC8620689 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Precision Medicine in Phaeochromocytoma and Paraganglioma.

Winzeler Bettina B Challis Benjamin G BG Casey Ruth T RT

Journal of personalized medicine 20211122 11

Precision medicine is a term used to describe medical care, which is specifically tailored to an individual patient or disease with the aim of ensuring the best clinical outcome whilst reducing the risk of adverse effects. Phaeochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumours with uncertain malignant potential. Over recent years, the molecular profiling of PPGLs has increased our understanding of the mechanisms that drive tumorigenesis. A high proportion of PPGLs are heredit ...[more]

PMID: 34834591

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Project description:Phaeochromocytomas and paragangliomas (collectively termed PPGL) are rare yet highly heritable neuroendocrine tumours, with over one-third of cases associated with germline pathogenic variants (PVs) in numerous genes. PVs in the succinate dehydrogenase subunit-A gene (SDHA) were initially implicated in hereditary PPGL in 2010, and SDHA has since become an important susceptibility gene accounting for up to 2.8% of cases. However, it remains poorly understood, particularly regarding the clinical nature of SDHA PPGL, rates of recurrence and metastasis, and the nature of metastatic disease. We present a narrative review of SDHA-related PPGL, covering pathophysiology, relevance to current clinical practice, and considerations for clinical genetics. We analyse a pool of 107 previously reported cases of SDHA-associated PPGL to highlight the spectrum of SDHA-related PPGL. Our analysis demonstrates that SDHA PPGL occurs across a wide age range (11-81 years) and affects men and women equally. SDHA PPGL typically presents as single tumours (91%), usually occurring in the head and neck (46%) or abdomen (43%, including 15% with phaeochromocytomas). Metastatic disease was reported in 25.5% of cases, with bone (82%) and lymph nodes (71%) being the most common sites of metastasis, often identified many years after the initial diagnosis. A family history of SDHA-related neoplasia was rare, reported in only 4% of cases. Understanding the clinical nature and risks associated with SDHA PVs is essential for facilitating the optimal management of patients and their families.

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Phaeochromocytoma/paraganglioma and adverse clinical outcomes in patients with neurofibromatosis-1.

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SDH mutations in tumorigenesis and inherited endocrine tumours: lesson from the phaeochromocytoma-paraganglioma syndromes.

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Using parenclitic networks on phaeochromocytoma and paraganglioma tumours provides novel insights on global DNA methylation.

Project description:Despite the prevalence of sequencing data in biomedical research, the methylome remains underrepresented. Given the importance of DNA methylation in gene regulation and disease, it is crucial to address the need for reliable differential methylation methods. This work presents a novel, transferable approach for extracting information from DNA methylation data. Our agnostic, graph-based pipeline overcomes the limitations of commonly used differential methylation techniques and addresses the "small n, big k" problem. Pheochromocytoma and Paraganglioma (PPGL) tumours with known genetic aetiologies experience extreme hypermethylation genome wide. To highlight the effectiveness of our method in candidate discovery, we present the first phenotypic classifier of PPGLs based on DNA methylation achieving 0.7 ROC-AUC. Each sample is represented by an optimised parenclitic network, a graph representing the deviation of the sample's DNA methylation from the expected non-aggressive patterns. By extracting meaningful topological features, the dimensionality and, hence, the risk of overfitting is reduced, and the samples can be classified effectively. By using an explainable classification method, in this case logistic regression, the key CG loci influencing the decision can be identified. Our work provides insights into the molecular signature of aggressive PPGLs and we propose candidates for further research. Our optimised parenclitic network implementation improves the potential utility of DNA methylation data and offers an effective and complete pipeline for studying such datasets.

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Clinical Practice Guidance: Surveillance for phaeochromocytoma and paraganglioma in paediatric succinate dehydrogenase gene mutation carriers.

Project description:The succinate dehydrogenase (SDH) enzyme complex functions as a key enzyme coupling the oxidation of succinate to fumarate in the citric acid cycle. Inactivation of this enzyme complex results in the cellular accumulation of the oncometabolite succinate, which is postulated to be a key driver in tumorigenesis. Succinate accumulation inhibits 2-oxoglutarate-dependent dioxygenases, including DNA and histone demethylase enzymes and hypoxic gene response regulators. Biallelic inactivation (typically resulting from one inherited and one somatic event) at one of the four genes encoding the SDH complex (SDHA/B/C/D) is the most common cause for SDH deficient (dSDH) tumours. Germline mutations in the SDHx genes predispose to a spectrum of tumours including phaeochromocytoma and paraganglioma (PPGL), wild type gastrointestinal stromal tumours (wtGIST) and, less commonly, renal cell carcinoma and pituitary tumours. Furthermore, mutations in the SDHx genes, particularly SDHB, predispose to a higher risk of malignant PPGL, which is associated with a 5-year mortality of 50%. There is general agreement that biochemical and imaging surveillance should be offered to asymptomatic carriers of SDHx gene mutations in the expectation that this will reduce the morbidity and mortality associated with dSDH tumours. However, there is no consensus on when and how surveillance should be performed in children and young adults. Here, we address the question: "What age should clinical, biochemical and radiological surveillance for PPGL be initiated in paediatric SDHx mutation carriers?".

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2023-12-21 | E-MTAB-13433 | biostudies-arrayexpress

Current Management of Pheochromocytoma/Paraganglioma: A Guide for the Practicing Clinician in the Era of Precision Medicine.

Project description:Pheochromocytomas and paragangliomas (PCC/PGLs) are rare, mostly catecholamine-producing neuroendocrine tumors of the adrenal gland (PCCs) or the extra-adrenal paraganglia (PGL). They can be separated into three different molecular clusters depending on their underlying gene mutations in any of the at least 20 known susceptibility genes: The pseudohypoxia-associated cluster 1, the kinase signaling-associated cluster 2, and the Wnt signaling-associated cluster 3. In addition to tumor size, location (adrenal vs. extra-adrenal), multiplicity, age of first diagnosis, and presence of metastatic disease (including tumor burden), other decisive factors for best clinical management of PCC/PGL include the underlying germline mutation. The above factors can impact the choice of different biomarkers and imaging modalities for PCC/PGL diagnosis, as well as screening for other neoplasms, staging, follow-up, and therapy options. This review provides a guide for practicing clinicians summarizing current management of PCC/PGL according to tumor size, location, age of first diagnosis, presence of metastases, and especially underlying mutations in the era of precision medicine.

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Investigating the role of somatic sequencing platforms for phaeochromocytoma and paraganglioma in a large UK cohort.

Project description:ObjectivesPhaeochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumours with malignant potential and a hereditary basis in almost 40% of patients. Germline genetic testing has transformed the management of PPGL enabling stratification of surveillance approaches, earlier diagnosis and predictive testing of at-risk family members. Recent studies have identified somatic mutations in a further subset of patients, indicating that molecular drivers at either a germline or tumour level can be identified in up to 80% of PPGL cases. The aim of this study was to investigate the clinical utility of somatic sequencing in a large cohort of patients with PPGL in the United Kingdom.Design and patientsProspectively collected matched germline and tumour samples (development cohort) and retrospectively collected tumour samples (validation cohort) of patients with PPGL were investigated.MeasurementsClinical characteristics of patients were assessed and tumour and germline DNA was analysed using a next-generation sequencing strategy. A screen for variants within 'mutation hotspots' in 68 human cancer genes was performed.ResultsOf 141 included patients, 45 (32%) had a germline mutation. In 37 (26%) patients one or more driver somatic variants were identified including 26 likely pathogenic or pathogenic variants and 19 variants of uncertain significance. Pathogenic somatic variants, observed in 25 (18%) patients, were most commonly identified in the VHL, NF1, HRAS and RET genes. Pathogenic somatic variants were almost exclusively identified in patients without a germline mutation (all but one), suggesting that somatic sequencing is likely to be most informative for those patients with negative germline genetic test results.ConclusionsSomatic sequencing may further stratify surveillance approaches for patients without a germline genetic driver and may also inform targeted therapeutic strategies for patients with metastatic disease.

| S-EPMC9543043 | biostudies-literature

A comprehensive characterisation of phaeochromocytoma and paraganglioma tumours through histone protein profiling, DNA methylation and transcriptomic analysis genome wide.

Project description:BackgroundPhaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours. Pathogenic variants have been identified in more than 15 susceptibility genes; associated tumours are grouped into three Clusters, reinforced by their transcriptional profiles. Cluster 1A PPGLs have pathogenic variants affecting enzymes of the tricarboxylic acid cycle, including succinate dehydrogenase. Within inherited PPGLs, these are the most common. PPGL tumours are known to undergo epigenetic reprograming, and here, we report on global histone post-translational modifications and DNA methylation levels, alongside clinical phenotypes.ResultsOut of the 25 histone post-translational modifications examined, Cluster 1A PPGLs were distinguished from other tumours by a decrease in hyper-acetylated peptides and an increase in H3K4me2. DNA methylation was compared between tumours from individuals who developed metastatic disease versus those that did not. The majority of differentially methylated sites identified tended to be completely methylated or unmethylated in non-metastatic tumours, with low inter-sample variance. Metastatic tumours by contrast consistently had an intermediate DNA methylation state, including the ephrin receptor EPHA4 and its ligand EFNA3. Gene expression analyses performed to identify genes involved in metastatic tumour behaviour pin-pointed a number of genes previously described as mis-regulated in Cluster 1A tumours, as well as highlighting the tumour suppressor RGS22 and the pituitary tumour-transforming gene PTTG1.ConclusionsCombined transcriptomic and DNA methylation analyses revealed aberrant pathways, including ones that could be implicated in metastatic phenotypes and, for the first time, we report a decrease in hyper-acetylated histone marks in Cluster 1 PPGLs.

| S-EPMC10734084 | biostudies-literature

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